Benzothiophene derivative

ABSTRACT

A benzothiophene derivative represented by the formula ##STR1## or a salt thereof has an excellent antiestrogenic activity, and is useful as a therapeutic agent of breast cancer, endometrial cancer, endometriosis, mastopathy, etc. 
     This compound is characterized in that the 2-position (the substituent R 2 ) of the benzothiophene nucleus is substituted by a halogen atom; a lower alkyl group; or a cycloalkyl or cycloalkenyl group optionally substituted by a lower alkyl group, a hydroxyl group, acyloxy group or an oxo group.

TECHNICAL FIELD

This invention relates to novel benzothiophene derivatives having anantiestrogenic activity, and relates more detailedly to benzothiophenederivatives represented by the formula ##STR2## wherein,

R¹ denotes a hydrogen atom, a hydroxyl group, a lower alkoxy group, anacyloxy group or an N,N-di-lower alkyl-substituted or unsubstitutedcarbamoyloxy group,

R² denotes a halogen atom; a lower alkyl group; or a cycloalkyl orcycloalkenyl group optionally substituted by a lower alkyl group, ahydroxyl group, an acyloxy group or an oxo group,

R³ and R⁴ each denote a hydrogen atom or a lower alkyl group, or R³ andR⁴ combine with the nitrogen atom to which they bind, to denote aheterocyclic ring which may further contain a hetero atom selected fromO, S and N,

A denotes O or CH₂,

B denotes C═O or CH₂, and

n denotes 1 or 2.

BACKGROUND ART

In gynecologic cancers such as breast cancer and endometrial cancer, theactivities of the estrogen receptor and the estrogen-biosynthesizingenzyme in the tumor tissue are higher than those in the normal mammarygland tissue and the endometrial tissue, and the proliferation of thesetumors have close relation to endogenous or local increase of estrogenicactivity. Thus as one means for therapy of gynecologic cancers, it isput into practice to make competition against the estrogenic effect inthe estrogenic target tissue, namely to administer antiestrogenicagents.

Among these antiestrogenic agents, a compound of the following formulacalled tamoxifen was, first, proposed (see, UK Patent No. 1,013,907).##STR3## Tamoxifen is now widely used for treatment of breast cancer,etc. as a representative antiestrogenic agent. Thereafter, several kindsof compounds having the same characteristic as tamoxifen is chemicalstructure, namely three benzene rings were proposed as antiestrogenicagents (see, for example, Proc. Soc. Exp. Biol. Med., 112, 439-442(1963), J. Med. Chem. 8, 725-726 (1965), J. Med. Chem., 22, 962-966(1979)).

Further, several benzothiophene derivatives having an antiestrogenicactivity have been known (see, Japanese Laid-Open Patent Publication No.181081/1982, Life Sci., 26, 1453-1458, 1980). Among them, a compound ofthe following formula called raloxifene has a very strong antiestrogenicactivity, and is now under clinical tests. ##STR4##

However, all of these antiestrogenic agents also have an estrogenicactivity too strong to be neglected, simultaneously with theantiestrogenic activity, and they were yet unsatisfactory in this point.

The present inventors have intensely researched for benzothiophenederivatives having an antiestrogenic activity, and as a result havefound that a series of compounds wherein a specific substituent such asa cycloalkyl group or a lower alkyl group was introduced in place of asubstituted phenyl group so far known as the substituent as the2-position of the benzothiophene nucleus have a strong antiestrogenicactivity but have only a very weak estrogenic activity.

DISCLOSURE OF INVENTION

The term "lower" in this description means that the carbon atom numberof a group or compound to which this term was attached is 6 or less,preferably 4 or less.

In the above formula (I), the "lower alkyl group" can be straight-chainor branched chain, and there can, for example, be mentioned a methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl orn-hexyl group or the like, and as the "lower alkoxy group", there can,for example, be mentioned a methoxy, ethoxy, n-propoxy, isopropoxy orn-butoxy group or the like. Further, as the "cycloalkyl group", thosehaving 3 to 12 preferably 3 to 8 carbon atoms are preferable, and therecan, for example, be mentioned a cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl group or the like, and as the"cycloalkenyl group", those having 4 to 12, preferably 5 to 8 carbonatoms are preferable, and there can, for example, be mentioned a1-cyclopentenyl, 1-cyclohexenyl, 1-cycloheptenyl or 1-cyclooctenyl groupor the like. Further, the "halogen atom" includes a fluorine, chlorine,or bromine atom.

The "acyloxy group" is specifically a group represented by the formulaR⁷ CO--O-- or R⁸ SO₂ --O--, and therein R⁷ denotes a hydrogen atom; alower alkyl group optionally substituted by a halogen atom, an aminogroup, a carbonyl group, a lower alkoxycarbonyl group, a loweralkanoyloxy group, a carbamoyl group or an aryl group; a lower alkenylgroup optionally substituted by an aryl group; a lower cycloalkyl group;or an aryl group optionally substituted by a lower alkyl group, a loweralkoxy group or a halogen atom, or the like, R⁸ denotes an aryl groupoptionally substituted by a lower alkyl group, or the like.

As examples of the "acyloxy group", there can be mentioned acetoxy,propionyloxy, trifluoroacetyloxy, glycyloxy, 3-carboxypropionyloxy,3-ethoxycarbonylpropionyloxy, acetoxyacetoxy, phenylacetoxy,acryloyloxy, cyclohexanecarbonyloxy, benzoyloxy, 4-methoxybenzoyloxy,2-chlorobenzoyloxy, methanesulfonyloxy and p-toluenesulfonyloxy groups,etc.

Further, when R² denotes "a cycloalkyl or cycloalkenyl group optionallysubstituted by a lower alkyl group, a hydroxyl group, an acyloxy groupor an oxo group", the cycloalkyl or cycloalkenyl group can be acycloalkyl or cycloalkenyl group unsubstituted or substituted by onelower alkyl, hydroxyl, acyloxy or oxo group, and therein, as thesubstituted cycloalkyl or cycloalkenyl group, there can, for example, bementioned a 3-methylcyclopentyl, 3-hydroxycyclopentyl,2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl,4-hydroxycyclohexyl, 4-acetoxycyclohexyl, 4-benzoyloxycyclohexyl,4-oxocyclohexyl or 2-methylcycloheptyl group or the like.

When, in the above formula (I), R³ and R⁴ "combine with the nitrogenatom to which they bind, to denote a heterocyclic ring which may furthercontain a hetero atom selected from O, S and N", the heterocyclic groupmay be substituted by a lower alkyl group or a hydroxyl group, or may bea condensed ring with a benzene ring. Further, in the heterocyclicgroup, the nitrogen atom-containing ring is preferably a 5- to7-membered heterocyclic ring.

Thus, as examples of the group ##STR5## there can be mentioned amino,methylamino, isopropylamino, dimethylamino, diethylamino, pyrrolidinyl,piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,3-methylpyrrolidinyl, 3-methylpiperidinyl, 4-hydroxypiperidinyl,4-methylpiperazinyl, 4-ethylpiperazinyl, 2,3-dihydroindolyl or1,2,3,4-tetrahydroisoquinolyl group or the like.

A preferred group of compounds among the compounds of the above formula(I) are compounds of the formula (I) wherein R¹ denotes a hydroxylgroup. Further, another preferred group of compounds are compounds ofthe formula (I) wherein R² denotes a branched chain lower alkyl group,particularly a group of the formula ##STR6## (wherein R⁵ and R⁶ eachdenote a lower alkyl group), or a cycloalkyl group having 3 to 8 carbonatoms optionally substituted by a lower alkyl group or a hydroxyl group.

As specific examples of the compounds of the above formula (I) providedby this invention, the following ones can be mentioned besides those setforth in the later-described examples.

(6-hydroxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-[1-(4-methylpiperazinyl)]ethoxy]phenyl]methanone,

(6-hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-[1-(3-methylpyrrolidinyl)]ethoxy]phenyl]methanone,

(6-hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(N-thiomorpholinyl)-ethoxy]phenyl]methanone,

(6-methanesulfonyloxy-2-cyclohexylbenzo[b]-thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone,

(6-hydroxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(N-morpholinyl)ethoxy]phenyl]methanone,

(6-hydroxy-2-cyclooctylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone,

(6-hydroxy-2-cyclododecylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone,

[6-hydroxy-2-(2-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(dimethylamino)ethoxy]phenyl]methanone,

[6-hydroxy-2-(4-hydroxycyclohexyl)benzo[b]-thien-3-yl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone,

[6-hydroxy-2-(4-hydroxycyclohexyl)benzo[b]-thien-3-yl][4-[2-(1-homopiperidinyl)ethoxy]phenyl]methanone,

(6-hydroxy-2-isopropylbenzo[b]thien-3-yl)[4-[2-(diethylamino)ethoxy]phenyl]methanone,

(6-hydroxy-2-isopropylbenzo[b]thien-3-yl)[4-[2-(1-homopiperidinyl)ethoxy]phenyl]methanone,

(6-hydroxy-2-sec-butylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone,

(6-hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(dimethylamino)propoxy]phenyl]methanone,

[6-hydroxy-2-(3-methylcyclohexyl)benzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methanone,

(6-hydroxy-2-isopropylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propoxy]phenyl]methanone,

(6-hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(diethylcarbamoyl)ethyl]phenyl]methanone,

[6-hydroxy-2-(3-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinylcarbonyl)ethyl]phenyl]methanone,

(6-hydroxy-2-isopropylbenzo[b]thien-3-yl)[4-[2-(1-piperidinylcarbonyl)ethyl]phenyl]methanone,

(6-hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-homopiperidinyl)propyl]phenyl]methanone,

(6-hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(N-morpholinyl)propyl]phenyl]methanone,

(6-hydroxy-2-isopropylbenzo[b]thien-3-yl)[4-[3-(1-pyrrolidinyl)propyl]phenyl]methanone,

(6-hydroxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[3-(1-pyrrolidinylcarbonyl)propyl]phenyl]methanone,

[6-hydroxy-2-(2-methylcyclohexyl)benzo[b]thien-3-yl][4-[3-(1-piperidinylcarbonyl)propyl]phenyl]methanone,

(6-hydroxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[4-(1-piperidinyl)butyl]phenyl]methanone,

(6-hydroxy-2-isopropylbenzo[b]thien-3-yl)[4-[4-(1-pyrrolidinyl)butyl]phenyl]methanone.

According to this invention, the compounds of the above formula (I)wherein B denotes CH₂ can be converted to salts. As examples of suchsalts, there can be mentioned acid addition salts with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acidand phosphoric acid; or organic acids such as acetic acid, propionicacid, succinic acid, maleic acid, benzoic acid, lactic acid, tartaricacid, citric acid and methanesulfonic acid, and among them,pharmacologically acceptable salts are preferable.

According to this invention, a compound of the above formula (I) or asalt thereof can, for example, be prepared by either

(a) reacting a compound of the formula ##STR7## wherein R¹¹ denotes ahydrogen atom or a lower alkoxy group, and R² has the same meaning asabove, with a compound of the formula ##STR8## wherein X¹ and X² eachdenote a halogen atom, and A, B and n have the same meanings as above,and then reacting the resultant compound of the formula ##STR9## whereinR¹¹, R², A, B, X² and n have the same meaning as above, with an amine ofthe formula ##STR10## wherein R³ and R⁴ have the same meanings as above,or

(b) reacting a compound of the above formula (II) with a compound of theformula ##STR11## wherein R³, R⁴, A, B, X¹ and n have the same meaningsas above, and then

(c) if necessary, converting the ring R¹¹ of the resultant compound ofthe formula ##STR12## wherein R¹¹, R², R³, R⁴, A, B and n have the samemeanings as above, to a hydroxyl group, an acyloxy group or anN,N-di-lower alkyl substituted or unsubstituted carbamoyloxy group, andfurther if necessary, converting the resultant compound to a salt.

According to the above process (a), first, the compound of the aboveformula (II) and the compound of the formula (III) are reacted.

The reaction can be carried out according to the Friedel-Craft'sacylation reaction, and specifically, can be carried out in an inertorganic solvent, for example, a halogenated hydrocarbon such asdichloromethane, 1,2-dichloroethane or chloroform; an aromatichydrocarbon such as benzene or chlorobenzene; an alkane such aspetroleum ether or hexane; a nitrohydrocarbon such as nitrobenzene ornitromethane; or the like, in the presence of a catalyst, for example, aLewis acid such as aluminum chloride, aluminum bromide, zinc chloride,boron trifluoride, titanium tetrachloride or stannic chloride. Properreaction temperature therefor is generally about room temperature to thereflux temperature of the reaction mixture, preferably a temperaturebetween room temperature and 100° C.

As to the use quantity of the compound of the above formula (III) to thecompound of the above formula (II), it is advantageous to use generallyat least one mole, preferably 1.1 to 5 moles of the compound of theformula (III) per mole of the compound of the formula II).

Further, as to the use quantity of the catalyst, it is preferable to useat least one, usually 1.5 to 10 moles of the catalyst per mole of thecompound of the above formula (II).

Thus, the compound of the above formula (IV) is obtained, and thiscompound is then reacted with the amine of the above formula (V).

The reaction of the compound of the above formula (IV) with the amine ofthe above formula (V) can generally be carried out in the absence ofsolvent, or in an inert solvent, for example, an ether such as ethylether, tetrahydrofuran or dioxane; an amide such as dimethylformamide ordimethylacetamide; an aromatic hydrocarbon such as benzene or toluene;dimethyl sulfoxide; or the like. Proper reaction temperature therefor isusually room temperature to the reflux temperature of the reactionmixture, preferably 35° C. to the reflux temperature of the reactionmixture.

As to the use quantity of the amine of the above formula (V) to thecompound of the above formula (IV), it is suitable to use generally atleast one mole, usually on the order of 1.5 to 10 moles of the amine ofthe formula (V) per mole of the compound of the formula (IV). When thereaction is carried out in the absence of solvent, it is possible to usethe amine of the formula (V) in an excess quantity and thereby make theamine play a role as a solvent.

Further, it is preferable to carry out the above reaction in thepresence of a deacidifying agent, for example, an organic base such aspyridine or triethylamine, or an inorganic base such as potassiumcarbonate or sodium carbonate, but it is usual to use the amine in anexcess quantity and thereby make the amine play a role as a deacidifyingagent.

According to the above process (b), the compound of the above formula(II) and the compound of the above formula (VI) are reacted.

The reaction can be carried out in the same manner as described in thereaction of the compound of the above formula (II) with the compound ofthe above formula (III) in the above process (a).

Thus, the compound in the case where R¹ in the compounds of the aboveformula (I) aimed at by this invention denotes a hydrogen atom or alower alkoxy group, namely the compound of the above formula (I-1) isobtained, and this compound can, if necessary, be converted to acompound of the above formula (I) in the case where R¹ denotes ahydroxyl group, an acyloxy group or an N,N-di-lower alkyl-substituted orunsubstituted carbamoyloxy group.

The conversion to the compound of the above formula (I) wherein R¹denotes a hydroxyl group can be carried out by subjecting the compoundof the above formula (I-1) wherein R¹¹ denotes a lower alkoxy group todealkylation reaction.

The dealkylation reaction can generally be carried out by treating thecompound of the above formula (I-1) in an inert solvent, for example ahalogenated hydrocarbon such as dichloromethane or chloroform; anaromatic hydrocarbon such as benzene or toluene; or the like, in thecoexistence of a sulfur compound such as ethanethiol or dimethyl sulfideand a Lewis acid such as aluminum chloride or boron trifluoride at anelevated temperature, preferably at the reflux temperature of thereaction mixture.

Further, the conversion to the compound of the above formula (I) whereinR¹ denotes an acyloxy group can easily be carried out by acylating thecompound of the above formula (I) wherein R¹ denotes a hydroxyl groupaccording to a process known per se, for example by reacting thecompound with an acyl halide in pyridine.

Further, the conversion to the compound of the above formula (I) whereinR¹ denotes an N,N-di-lower alkyl-substituted or unsubstitutedcarbamoyloxy group can also be carried out easily by a process known perse, for example by reacting the compound of the above formula (I)wherein R¹ denotes a hydroxyl group with a substituted or unsubstitutedcarbamoyl chloride in pyridine.

In the compounds of the above formula (I) prepared according to theabove-described processes, a compound wherein B denotes CH₂ can beconverted to a corresponding salt by treating it with an inorganic acidor an organic acid according to a process known per se.

The thus obtainable compound of the above formula (I) can be separatedfrom the reaction mixture and purified by methods such as, for example,extraction, filtration, distillation, recrystallization, columnchromatography and thin layer chromatography.

A compound in the case where B denotes CH₂ in the compounds of the aboveformula (I-1) of this invention can, alternatively, be prepared byreducing a compound of the following formula ##STR13## wherein R¹¹, R²,R³, R⁴, A and n have the same meanings as above, and then oxidizing theresultant compound.

The reduction of the compound of the formula (I-2) can, for example, becarried out by treating it with lithium aluminum hydride in a solventsuch as tetrahydrofuran or dioxane under reflux with heating. Theoxidation of the resultant compound of the following formula ##STR14##wherein R¹¹, R², R³, R⁴, A and n have the same meanings as above, caneasily be carried out by treating it with chromium trioxide in pyridine.

In the compounds of the above formula (I) of this invention, a compoundwherein R² denotes a cycloalkyl or cycloalkenyl group substituted by ahydroxyl group can, for example, be prepared by reducing a compound ofthe formula (I) Wherein R² denotes a cycloalkyl or cycloalkenyl groupsubstituted by an oxo group with a complex metal hydride such as sodiumborohydride in a solvent such as tetrahydrofuran.

Further, a compound of the formula (I) wherein R² is a cycloalkyl orcycloalkenyl group substituted by an acyloxy group can be prepared byacylating a compound of the formula (I) wherein R² is a cycloalkyl orcycloalkenyl group substituted by a hydroxyl group, according to aprocess known per se. In this reaction, when a compound of the formula(I) wherein R¹ is a hydroxyl group is used, R¹ is acylatedsimultaneously and converted to an acyloxy group.

Among the compounds of the above formula (II) used as a startingcompound in the foregoing processes, compounds wherein R¹¹ denotes alower alkoxy group, namely compounds of the following formula ##STR15##wherein R¹² denotes a lower alkoxy group and R² has the same meaning asabove, are novel compounds not disclosed in the past literatures, andare important intermediates for synthesis of the compounds of the aboveformula (I) of this invention having a strong antiestrogenic activity.

The compounds of the above formula (II) as a starting material for thecompounds of this invention can, for example, by synthesized accordingto the following Reaction formula 1. ##STR16##

In the above formulae, R_(a) and R_(b) each denote a lower alkyl group,or combine with the carbon atom to which they bind to denote acycloalkyl group optionally substituted by a lower alkyl group or an oxogroup, and R¹¹ has the same meaning as above.

As to the detail of reaction conditions in Reaction formula 1, pleasesee the later-described preparation examples.

Further, a compound of the formula (II) wherein R² denotes a cycloakylor cycloalkenyl group substituted by a hydroxyl group or an acyloxygroup can be synthesized by converting a compound wherein R² denotes acycloalkyl or cycloalkenyl group substituted by an oxo group, in thesame manner as described in the conversion of R² in a compound of theformula (I).

Effect of the Invention

The thus described benzothiophene derivatives represented by the formula(I) of this invention have an excellent antiestrogenic activity, and areeffective for curing or treatment of estrogen-dependent diseases suchas, for example, breast cancer, endometrial cancer, endometriosis,prostatic hypertrophy and mastopathy.

The antiestrogenic activities of the compounds of the formula (I) ofthis invention are as follows.

Assay of Antiestrogenic Activity

Assay was carried out according to the juvenile rat uterus weight methodusing groups of immature female rats (weight 50 to 60 g), each groupconsisting of 5 animals.

Namely, 2 μg/animal of estradiol and a test compound were subcutaneouslyadministered to rats once a day for 3 days, the rats were killed on thefourth day, and each uterus was weighed. Antiestrogenic activity wasassessed depending on whether or not the weight of the uterus of thegroup to which estradiol and the test compound were administered issignificantly inhibited in comparison with the weight of the uterus ofthe group to which estradiol alone was administered.

The results are shown in the following table. As to antiestrogenicactivity, when 0.1 mg/kg each of test compounds were administered, thoseinhibiting the uterine weight significantly at a level of significanceof 1% and those inhibiting the uterine weight significantly at a levelof significance of 5% were expressed by ++ and +, respectively.

                  TABLE                                                           ______________________________________                                        Compound     Antiestrogenic activity                                          ______________________________________                                        Example 71   ++                                                               Example 74   ++                                                               Example 75   ++                                                               Example 76   ++                                                               Example 77   ++                                                               Example 86   ++                                                               Example 87   ++                                                               Example 90   ++                                                               Example 91   ++                                                               Example 93   +                                                                Example 96   +                                                                Example 104  +                                                                Example 115  +                                                                Example 118  ++                                                               Example 120  ++                                                               Example 123  +                                                                Example 124  ++                                                               Example 130  +                                                                ______________________________________                                    

Thus, the compounds of this invention represented by the formula (I) canbe orally or parenterally (for example, intramuscularly, intravenously,rectally, transcutaneously, or the like) administered as anantiestrogenic agent for curing or treatment of human beings and othermammals.

The compounds of this invention, when used as a drug, can be used byformulating them into any dosage form of solid forms (e.g., tablets,hard capsules, soft capsules, granules, powders, fine granules, pills,troches, etc.), semi-solid forms (e.g., suppositories, ointments, etc.)and liquid forms (e.g., injections, emulsions, suspensions, lotions,sprays, etc.). An nontoxic additives usable in the above formulations,there can, for example, be mentioned starches, gelatin, glucose,lactose, fructose, maltose, magnesium carbonate, talc, magnesiumstearate, methylcellulose, carboxymethylcellulose or salts thereof, gumarabic, polyethylene glycol, p-hydroxybenzoic acid alkyl esters, syrups,ethanol, propylene glycol, vaselines, carbowax, glycerol, sodiumchloride, sodium sulfite, sodium phosphate, citric acid, etc. The drugcan also contain another therapeutically effective drug.

The content of the compound of this invention in the drug variesdepending on the dosage form, but it is generally preferable that thedrug contains the compound at a concentration of 0.1 to 50 wt. % in thecase of solid and semi-solid forms, and at a concentration of 0.05 to 10wt. % in the case of liquid form.

The dose of the compound of this invention can widely be varieddepending on the kind of warm-blooded animals including human beings asa subject, administration routes, the seriousness of symptoms, thediagnoses of doctors, etc., but can be generally 0.05 to 50 mg/kg,preferably 0.1 to 10 mg/kg per day. However, it is of course be possibleto administer the compound in an amount smaller than the lower limit ofthe above range or in an amount larger than the upper limit thereof inaccordance with the seriousness of the symptom of the patient and thediagnosis of the doctor as mentioned above. The above dose can beadministered once a day or in divided several portions per day.

This invention is further described below according to examples andpreparation examples.

Preparation Example 1

3.2 g of 6-methoxybenzo[b]thiophene was dissolved in 3 ml of THF and thesolution was cooled with ice. 18.6 ml of n-butyllithium (15% hexanesolution) was gradually added in a stream of nitrogen and the mixturewas stirred. A THF solution of 3.1 ml of cyclohexanone was added and themixture was stirred at room temperature for 6 hours. 35 ml of saturatedaqueous ammonium chloride solution was added to the reaction mixture,the resultant mixture was extracted with ether, and the extract wasdried over anhydrous magnesium sulfate. The solvent was distilled off,and the resultant crude product was purified by TLC (developing solvent,chloroform) to obtain 2.8 g of6-methoxy-2-(1-hydroxycyclohexyl)benzo[b]thiophene.

¹ H-NMR(CDCl₃, δ):1.33˜2.03(10H, m), 3.85(3H, s), 6.94(1H, dd, J=2.4,8.6 Hz), 7.09(1H, s), 7.27(1H, d, J=2.4 Hz), 7.57(1H, d, J=8.6 Hz).

MS(m/z):262(M⁺), 244, 219.

The following compounds of (i) to (ix) were synthesized in the samemanner as in Preparation example 1.

(i) 6-Methoxy-2-(1-hydroxycyclopentyl)benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.58˜2.86(8H, m), 3.85(3H, s), 6.86(1H, d, J=2.4 Hz),6.94(1H, s), 7.22(1H, d, J=2.4 Hz), 7.54(1H, d, J=8.6 Hz).

MS(m/z):248(M⁺), 230.

(ii)6-Methoxy-2-[4,4-(ethylenedioxy)-1-hydroxycyclohexyl]benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.30˜2.50(8H, m), 3.85(3H, s), 3.97(4H, s), 6.94 (1H,dd, 1:8.8, 2.4 Hz), 7. 10(1H, br, s), 7.27(1H, d, J:2.4 Hz), 7.55(1H, d,J=8.8 Hz).

MS(m/z):320(M⁺), 302, 216, 101.

(iii) 6-Methoxy-2-(1-hydroxycycloheptyl)benzo[b]thiophene

¹ H-NMR(CDCl₂ δ):1.46˜2. 71 (13H, m), 3.84(3H, s), 6.90(1H; dd, J=8.8,2.4 Hz), 7.07(1H, d. J=0.4 Hz), 7.20(1H, d, J=2.2Hz), 7.51(1H, d, J=8.6Hz).

Ms(m/z):276(M⁺), 258.

(iv) 6-Methoxy-2-[1-hydroxy-(2-methylcyclohexyl)]benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):0.82(3H, d, J=6.6 Hz), 1.54˜1.94(10H, m), 3.85(3H, s),6.94(1H, dd, J=8.6, 2.4 Hz), 7.03(1H, d, J=0.4 Hz), 7.26(1H, d, J=2.9Hz), 7.50(1H, d, J=8.6 Hz).

MS(m/z):276(M⁺), 219.

(v) 6-Methoxy-2-[1-hydroxy-(3-methylcyclohexyl)]benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):0.94(3H, d, J=6.2 Hz), 1.45˜2.11(10H, m), 3.85(3H, s),6.94(1H, dd, J=8.6, 2.4 Hz), 7.06(1H, d, J=0.4 Hz), 7.27(1H, d, J=2.9Hz), 7.56(1H, d, J=8.8 Hz).

MS(m/z):276(M⁺), 233.

(vi) 6-Methoxy-2-[1-hydroxy-(4-methylcyclohexyl)]benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.01(3H, d, J=5.9 Hz), 1.23˜2.56(10H, m), 3.89(3H, s),6.93(1H, dd, J=6.4, 1.8 Hz), 7.07(1H, d, J=O. 7 Hz), 7.20˜7.28(1H, m),7.66(1H, d, J=8.6 Hz).

MS(m/z):276(M⁺), 219.

(vii) 6-Methoxy-2-(1-hydroxycyclooctyl)]benzo[b]thiophene

¹ H-NMR(CDCl₃ δ):1.40˜1.88(10H, m), 2.10˜2.79(4H, m), 3.85(3H, s),6.18(1H, t, J=8.1 Hz), 6.89(1H, dd, J=8.8, 3.4 Hz), 7.05(1H, s), 7.21(1H, d, J=2.4 Hz), 7.52(1H, d, J=8.6 Hz).

MS(m/z):290(M⁺), 272, 244.

(viii) 6-Methoxy-2-(1-hydroxycyclododecyl)benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.23˜2.66(23H, m), 3.85(3H, s), 6.93(1H, dd, J=8.6,2.4 Hz), 7.03(1H, s), 7.25(1H, d, J=4.6 Hz), 7.51(1H, d, J=8.8 Hz).

MS(m/z):346(M⁺), 328, 204.

(ix) 6-Methoxy-2-(1-hydroxy-1-methylethyl)benzo[b]thiophene

Preparation Example 2

2.8 g of 6-methoxy-2-(1-hydroxycyclohexyl)benzo[b]thiophene wasdissolved in 25 ml of toluene, 320 mg of anhydrous oxalic acid wasadded, and the mixture was refluxed with heating for 1 hour. Thereaction mixture was washed twice with 5% aqueous sodium bicarbonatesolution and once with water, and dried over magnesium sulfate. Thesolvent was distilled off to obtain 20 2.5 g of6-methoxy-2-(1-cyclohexenyl)benzo[b]thiophene.

¹ H-NMR(CDCl₃, δ):1.49˜2.51(8H, m), 3.84(3H, s), 6.20(1H, br), 6.89 (1H,rid, J=2.4, 8.8 Hz), 7.00(1H, br), 7.21 (1H, d, J=2.4 Hz), 7.52(1H, d,J=8.8 Hz).

MS(m/z):244(M⁺).

The following compounds of (i) to (ix) were synthesized in the samemanner as in Preparation example 2.

(i) 6-Methoxy-2-(1-cyclopentenyl)benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.49˜2.89(6H, m), 3.85(3H, s), 6.05(1H, m), 6.86 (1H,dd, J=8.6, 2.4 Hz), 6.97(1H, s), 7.22(1H, d, J=2.4 Hz), 7.54(1H, d,J=8.6 Hz).

MS(m/z):230(M⁺), 215.

(ii) 6-Methoxy-2-(4-oxo-1-cyclohexenyl)benzo[b]thiophene

(iii) 6-Methoxy-2-( 1-cycloheptenyl)benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.47˜1.90(6H, m), 2.30(2H, q, J=6.8, 3.5 Hz),2.60˜2.71 (2H, m), 3.85(3H, s), 6.35(1H, t, J=6.8 Hz), 6.89(1H, dd,J=8.6, 2.4 Hz), 7.02(1H, s), 7.20(1H, d, J=2.2 Hz), 7.51(1H, d, J=8.6Hz).

MS(m/z):258(M⁺), 231.

(iv) 6-Methoxy-2-[1-(2-methylcyclohexenyl)]benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.21(3H, d, J=7.0 Hz), 1.52˜1.85(4H, m), 2.10˜2.29(2H,m), 2.75˜2.89(1H, br s), 3.85(3H, s), 6.11(1H, t, J=3.7 Hz), 6.90(1H,dd, J=8.6, 2.4 Hz), 7.02(1H, s), 7.22(1H, d, J=2.4 Hz), 7.53(1H, d,J=8.6 Hz).

MS(m/z):258(M⁺).

(v) 5-Methoxy-2-[1-(3-methylcyclohexenyl)]benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.07(3H, d, J=5.9 Hz), 1.24˜2.50(7H, m), 3.84(3H, s),6.11(1H, d, J=12.5 Hz), 6.90(1H, dd, J=8.6, 2.4 Hz), 7.01(1H, s), 7.21(1H, d, J=2.4 Hz), 7.52(1H, d, J=8.6 Hz).

MS(m/z):258(M⁺).

(vi) 6-Methoxy-2-[1-(4-methylcyclohexenyl)]benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.01(3H, d, J=5.7 Hz), 1.26˜2.59(7H, m), 3.84(3H, s),6.12˜6.19(1H, br s), 6.89(1H, dd, J=8.6, 2.4 Hz), 7.00(1H, s), 7.21 (1H,d, J=2.4 Hz), 7.52(1H, d, J=8.6 Hz).

MS(m/z):258(M⁺), 216.

(vii) 6-Methoxy-2-(1-cyclooctenyl)benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.54˜1.83(8H, m), 2.21˜2.40(2H, m), 2.69(2H, t, J=5.1Hz), 3.84(3H, s), 6.18(1H, t, J=8.1 Hz), 6.89(1H, dd, J=8.6, 2.4 Hz),7.04(1H, s), 7.21(1H, d, J=2.4 Hz), 7.52(1H, d, J=8.6 Hz).

MS(m/z):272(M⁺), 244.

(viii) 6-Methoxy-2-(1-cyclododecenyl)benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.23˜1.80(16H, m), 2.26(2H, q, J=7.5, 7.0 Hz), 2.59(2H, t, J=6.8 Hz), 3.84(3H, s), 5.93(1H, t, J=8.1 Hz), 6.90(1H, dd,J=8.6, 2.4 Hz), 7.04(1H, s), 7.21 (1H, d, J=2.4 Hz), 7.52(1H, d, J=8.6Hz).

MS(m/z):328(M⁺), 204.

(ix) 6-Methoxy-2-isopropenylbenzo[b]thiophene

Preparation Example 3

5 g of 6-methoxy-2-(1-cyclohexenyl)benzo[b]thiophene was dissolved in 20ml of ethyl acetate, 800 mg of 5% palladium-carbon was added, andhydrogenation was carried out at room temperature and at atmosphericpressure. The reaction mixture was filtered, and the filtrate wasconcentrated to obtain 2.5 g of 6-methoxy-2-cyclohexylbenzo[b]thiophene.

¹ H-NMR(CDCl₃, δ):1.15˜2.21(10H, m), 2.82(1H, m), 3.84(3H, s),6.83˜7.57(4H, m).

MS(m/z):246(M⁺).

The following compounds of (i) to (viii) were synthesized in the samemanner as in Preparation example 3.

(i) 6-Methoxy-2-cyclopentylbenzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.46˜2.30(8H, m), 3.27(1H, m), 3.84(3H, s), 6.91 (1H,s), 6.94(1H, dd, J=8.6, 2.4 Hz), 7.25(1H, d, J=2.4 Hz), 7.52(1H, d,J=8.6 Hz).

MS(m/z):232(M⁺), 203.

(ii) 6-Methoxy-2-(4-oxo-1-cyclohexyl)benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.50˜2.70(8H, m), 3.35(1H, m), 3.85(3H, s), 6.96 (1H,dd, J=8.6, 2.4 Hz), 6.98(1H, br s), 7.28(1H, d, J=2.4 Hz), 7.55(1H, d,J=8.6 Hz).

(iii) 6-Methoxy-2-cycloheptylbenzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.41˜2.25(12H, m), 2.89˜3.09(1H, m), 3.83(3H, s),6.91(1H, dd, J=8.6, 2.4 Hz), 6.87(1H, s), 7.24(1H, d, J=2.0 Hz),7.51(1H, d, J=8.6 Hz).

MS(m/z):260(M⁺), 203.

(iv) 6-Methoxy-2-(2-methylcyclohexyl)benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):0.80(3H, d, J=7.0 Hz), 1.20˜2.40(9H, m), 2.98˜3.13(1H,m), 3.83(3H, s), 6.85(1H, s), 6.91 (1H, dd, J=8.8, 2.4 Hz), 7.25(1H, d,J=2.4 Hz), 7.53(1H d, J=8.6 Hz).

MS(m/z):260(M⁺), 203.

(v) 5-Methoxy-2-(3-methylcyclohexyl)benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):0.95(3H, d, J=5.9 Hz), 1.19˜2.20(9H, m), 3.10˜3.28(1H,m), 3.84(3H, s), 6.88(1H, s), 6.91(1H, dd, J=8.6, 2.4 Hz), 7.25(1H, d,J=1.5 Hz), 7.52(1H, d, J=8.8 Hz).

MS(m/z):260(M⁺).

(vi) 6-Methoxy-2-(4-methylcyclohexyl)benzo[b]thiophene

¹ H-NMR(CDCl₃, δ):0.94(3H, d, J=6.4 Hz), 1.20˜2.20(9H, m), 2.95˜3.08(1H,m), 3.83(3H, s), 6.91 (1H, dd, J=8.6, 2.4 Hz), 6.94(1H, s), 7.24(1H, d,J=2.4 Hz), 7.52 (1H, d, J=8.8 Hz).

MS(m/z):260(M⁺), 203.

(vii) 6-Methoxy-2-cyclododecylbenzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.14˜1.97(22H, m), 3.01˜3.15(1H, m), 3.84(3H, s), 6.91(1H, dd, J=8.8, 2.4 Hz), 6.90(1H, s), 7.25(1H, d, J=2.2 Hz), 7.52(1H, d,J=8.6 Hz).

MS(m/z):330(M⁺).

(viii) 6-Methoxy-2-isopropylbenzo[b]thiophene

¹ H-NMR(CDCl₃, δ):1.37(6H, d, J=7.8 Hz), 3.04˜3.35(1H, m), 3.84(3H, s),6.92(1H, dd, J=8.6, 2.4 Hz), 6.89(1H, s), 7.25(1H, d, J=2.4 Hz),7.52(1H, d, J=8.6 Hz).

MS(m/z):206(M⁺), 191.

Preparation Example 4

The same operations as in Preparation example 1 were carried out using180 mg of 6-methoxybenzo[b]thiophene, and 450 mg of methyl iodide inplace of cyclohexanone, and then purification was carried out by TLC(developing solvent, chloroform:n-hexane=1:19) to obtain 126 mg of6-methoxy-2-methylbenzo[b]thiophene.

¹ H-NMR(CDCl₃, δ):2.53(3H, s), 3.85(3H, s), 6.85˜7.56(4H, m).

MS(m/z):164(M⁺).

Preparation Example 5

The same operations as in Preparation example 1 were carried out using495 mg of 6-methoxybenzo[b]thiophene, and chlorine gas in place ofcyclohexanone, and then purification was carried out by TLC (developingsolvent, chloroform:n-hexane=4:1) to obtain 172 mg of6-methoxy-2-chlorobenzo[b]thiophene.

¹ H-NMR(CDCl₃, δ):3.85(3H, s), 6.89˜7.73(4H, m).

MS(m/z):200, 198.

Preparation Example 5

50 mg of 4-(2-chloroethoxy)benzoic acid was refluxed with heatingtogether with 0.5 ml of thionyl chloride and 1 ml of 1,2-dichloroethanefor 2 hours to convert it to an acid chloride. The resultant acidchloride was concentrated under reduced pressure to distill off1,2-dichloroethane and thionyl chloride, and the residue was mixed with50 mg of 5-methoxy-2-cyclohexylbenzo[b]thiophene, 7 ml ofdichloromethane and 200 mg of aluminum chloride, followed by stirring atroom temperature for 3 hours. 1 ml of THF, 0.3 ml of 20% hydrochloricacid and 1 ml of water were added to the reaction mixture at 25° C. orlower, and the mixture was made alkaline with saturated aqueous sodiumbicarbonate solution and then extracted with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate, the solvent wasdistilled off, and the resultant crude product was purified by TLC(developing solvent, chloroform:n-hexane=2:1) to obtain 41 mg of(6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-(2-chloroethoxy)phenyl]methanone.

¹ H-NMR(CDCl₃, δ):1.09˜3.11(11H, m), 3.76˜3.88(5H, m), 3.83(3H, s),4.28(2H, t, J=5.5 Hz), 6.77˜8.04(7H, m).

MS(m/z):430, 428.

The following compounds of (i) to (ix) were synthesized in the samemanner as in Preparation example 6.

(i)(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-(2-chloropropoxy)phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.12˜2.41(12H, m), 3.00(1H, m), 3.74(2H, t, J=6 Hz)3.84(3H, s), 4.19(2H, t, J=6 Hz), 6.76˜8.04(7H, m).

MS(m/z):444, 442.

(ii)[6-Methoxy-2-(2-methylcyclohexyl)benzo[b]thien-3yl][4-(2-chloroethoxy)phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.72˜2.46(12H, m), 3.82(2H, t, J=5.8 Hz), 3.88(3H, s),4.31 (2H, t, J=5.8 Hz), 6.76˜8.04(7H, m).

MS(m/z):444, 442.

(iii)(6-Methoxy-2-cycloheptylbenzo[b]thien-3-yl)[4-(2-chloroethoxy)phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.26˜2.17(12H, m), 3.16(1H, m), 3.81(2H, t, J=5.7 Hz),3.84(3H, s), 4.28(2H, br t), 6.78˜8.08(7H, m).

MS(m/z):444, 442.

(iv)(6-Methoxy-2-cycloheptylbenzo[b]thien-3-yl)[4-(2-chloropropoxy)phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.26˜2.33(14H, m), 3.75(2H, t, J=6 Hz), 3.85(3H, s),4.19(2H, t, J=6 Hz), 6.78˜8.04(7H, m).

MS(m/z):458, 456.

(v)[6-Methoxy-2-(3-methylcyclohexyl)benzo[b]thien-3-yl][4-(2-chloroethoxy)phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.78˜2.08(12H, m), 3.81(2H, t, J=5.7 Hz), 3.83(3H, s),4.30(2H, br t), 6.78˜8.08(7H, m).

MS(m/z):444, 442.

(vi)(6-Methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-(2-chloroethoxy)phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.25˜2.21(8H, m), 3.33(1H, m), 3.75˜3.88(5H, m),4.28(2H, t, J=5.6 Hz), 6.79˜8.04(7H, m).

MS(m/z):416, 414.

(vii)(6-Methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-(2chloropropoxy)phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.22˜2.42(10H, m), 3.36(1H, m), 3.74(2H, t, J=5.9 Hz),3.84(3H, s), 4.18(2H, t, J=5.9 Hz), 6.79˜8.01 (7H, m).

MS(m/z):430, 428.

(viii)(6-Methoxy-2-cyclododecylbenzo[b]thien-3-yl)[4-(2-chloroethoxy)phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.15˜2.10(22H, m), 2.90˜3.20(1H, m), 3.76(3H, s),3.82(2H, t, J=5.3 Hz), 4.29(2H, t, J=5.5 Hz), 6.85(1H, dd, J=7.0, 2.2Hz), 6.90(2H, d, J=9.0 Hz), 7.25˜7.58(2H, m), 7.76(2H, d, J=9.0 Hz).

MS(m/z):512(M⁺), 329, 183.

(ix)(6-Methoxy-2-isopropylbenzo[b]thien-3-yl)[4-(2-chloroethoxy)phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.31(6H, d, J=6.8 Hz), 3.19˜3.49(1H, m), 3.83(2H, t,J=5.9 Hz), 3.85(3H, s), 4.30(2H, t, J=5.5 Hz), 6.93(1H, d, J=8.8 Hz),6.85(1H, dd, J=8.8, 2.4 Hz), 6.85˜6.96(1H, m), 7.24(2H, d, J=8.6 Hz),7.84(2H, d, J=9.0 Hz).

MS(m/z):388(M⁺), 373.

Preparation Example 7

353 mg of(6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinylcarbonyl)ethyl]phenyl]methanonewas dissolved in 30 ml of THF, 850 mg of lithium aluminum hydride wasadded, and the mixture was refluxed with heating for 1 hour. A smallquantity of water was added to the reaction mixture, followed bystirring, 1 ml of methanol was added, followed by stirring for 5minutes, and 5 ml of ethyl acetate was added, followed by stirring for 5minutes. The mixture was filtered using a super cell, the filtrate wasconcentrated under reduced pressure, and the resultant crude product waspurified by TLC (developing solvent, chloroform:methanol=19:1) to obtain107 mg of(6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propyl]phenyl]methanol.

¹ H-NMR(CDCl₃, δ):1.26˜2.86(26H, m), 3.4(1H, m), 3.85(3H, s), 6.26 (1H,s), 6.71˜7.60(7H, m).

MS(m/z):477(M⁺), 98.

The following compounds of (i) to (iv) were synthesized in the samemanner as in Preparation example 7.

(i)(6-Methoxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propyl]phenyl]methanol

¹ H-NMR(CDCl₃, δ):1.25˜2.80(28H, m), 3.34(1H, m), 3.80(3H, s), 6.26 (1H,s), 6.72˜7.53(7H, m).

MS(m/z):491(M⁺), 98.

(ii)(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(dimethylamino)propyl]phenyl]methanol

¹ H-NMR(CD₃ OD, δ):1.21˜2.05(10H, m), 2.29(6H, s), 2.29˜2.68(2H, m),3.47˜3.72(4H, m), 3.78(3H, s), 6.21(1H, s), 6.68˜7.58(7H, m).

MS(m/z):437(M⁺), 58.

(iii)(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-pyrrolidinyl)propyl]phenyl]methanol

¹ H-NMR(CDCl₃, δ):1.10˜2.05(16H, m), 2.45˜2.78(8H, m), 2.85˜3.50 (1H,m), 3.80(3H, s), 6.26(1H, s), 6.71˜7.52(7H, m).

MS(m/z):463(M⁺), 84.

(iv)(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[4-(1-pyrrolidinyl)butyl]phenyl]methanol

EXAMPLE 1

1 ml of pyrrolidine was added to 30 mg of(6-methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-(2-chloroethoxy)phenyl]methanone,followed by reflux with heating for 1 hour. The mixture was concentratedunder reduced pressure to distil off pyrrolidine, and the residue waspurified by TLC (developing solvent, chloroform:methanol= 19:1) toobtain 28 mg of(6-methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone.

¹ H-NMR(CDCl₃, δ):0.94˜2.47(12H, m), 2.55˜2.79(4H, m), 2.94(2H, t, J=6Hz), 3.41(1H, m), 3.84(3H, s), 4.19(2H, t, J=6 Hz), 6.79˜7.87(7H, m).

MS(m/z):449(M⁺), 84.

The following compounds of Examples 2-31 were synthesized in the samemanner as in Example 1.

EXAMPLE 2

(6-Methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(1-homopiperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.25˜2.16(16H, m), 2.77˜2.92(4H, m), 2.94(2H, t, J=6Hz), 3.3(1H, m), 3.84(3H, s), 4.12(2H, t, J=6 Hz), 6.79˜7.87(7H, m).

MS(m/z):477(M⁺), 112.

EXAMPLE 3

(6-Methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-[1-(3-methylpiperidinyl)]ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.89(3H, d, J=5.9 Hz), 1.25-2.23(15H, m),2.87˜3.60(5H, m), 3.84(3H, s), 4.26(2H, t, J=5.7 Hz), 6.79˜7.87(7H, m).

MS(m/z):477(M⁺), 112.

EXAMPLE 4

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-[1-(4-methylpiperazinyl)]ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.12˜2.07(10H, m), 2.32(3H, s), 2.37˜2.75(8H, m),2.84(2H, t, J=5.7 Hz), 3.84(3H, s), 4.17(2H, t, J=5.7 Hz), 6.77˜7.88(7H,m).

MS(m/z):492(M⁺), 113.

EXAMPLE 5

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-[2-(1,2,3,4-tetrahydroisoquinolinyl)]ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.10˜2.16(10H, m), 2.61˜3.09(7H, m), 3.84(5H, m),4.28(2H, t, J=5.7 Hz), 6.76˜7.87(11H, m).

MS(m/z):525(M⁺), 146.

EXAMPLE 6

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-[1-(4-hydroxypiperidinyl)]ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):112˜2.16(14H, m), 2.34˜3.07(7H, m), 3.69˜3.84 (4H, m),4.23(2H, t, J=5.7 Hz), 6.78˜7.86(7H, m).

MS(m/z):493(M⁺), 114.

EXAMPLE 7

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(diethylamino)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.77˜2. 13(16H, m), 2.72(4H, q), 2.96(2H, t, J=6 Hz),3.84(3H, s), 4.18(2H, t, J=6 Hz), 6.78˜7.85(7H, m).

MS(m/z):465(M⁺), 86.

EXAMPLE 8

(6-Methoxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.22˜2.24(16H, m), 2.55˜2.72(4H, m), 2.94(2H, t, J=5.9Hz), 3.2(1H, m), 3.84(3H, s), 4.19(2H, t, J=5.9 Hz), 6.78˜8.03(7H, m).

MS(m/z):477 (M⁺), 84.

EXAMPLE 9

(6-Methoxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(1-homopiperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.25˜2.16(20H, m), 2.79˜2.85(4H, m), 3.03(2H, t, J=5.9Hz), 3.84(3H, s), 4.18(2H, t, J=5.9 Hz), 6.78˜7.85(7H, m).

MS(m/z):505(M⁺), 112.

EXAMPLE 10

(6-Methoxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-[1-(3-methylpiperidinyl)]ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.92(3H, d, J=5.9 Hz), 1.12˜2.69(19H, m),2.60˜3.25(5H, m), 3.83(3H, s), 4.19(2H, t, J=5.9 Hz), 6.78˜8.00(7H, m).

MS(m/z):505(M⁺), 112.

EXAMPLE 11

[6-Methoxy-2-(2-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.84(3H, d, J=7.0 Hz), 1.13˜2.15(13H, m),2.57˜2.89(4H, m), 2.97(2H, t, J=5.8 Hz), 3.4(1H, m), 3.84(3H, s),4.21(2H, t, J=5.8 Hz), 6.77˜7.85(7H, m).

MS(m/z):477(M⁺), 84.

EXAMPLE 12

[6-Methoxy-2-(2-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.80(3H, d, J=7.0 Hz), 1.13˜2.29(15H, m), 2.53(4H, m),2.79(2H, t, J=6 Hz), 3.3(1H, m), 3.84(3H, s), 4.17(2H, t, J=6 Hz),6.77˜7.85(7H, m).

MS(m/z):491(M⁺), 98.

EXAMPLE 13

[6-Methoxy-2-(2-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-homopiperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.83(3H, d, J=7.0 Hz), 1.13˜2.07(17H, m),2.75˜2.88(4H, m), 3.01(2H, t, J=6.2 Hz), 3.4(1H, m), 3.84(3H, s),4.17(2H, t, J=6.2 Hz), 6.62˜7.85(7H, m).

MS(m/z):505(M⁺), 112.

EXAMPLE 14

[6-Methoxy-2-(3-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.88(3H, d, J=5.3 Hz), 1.03˜2.68(13H, m),2.72˜2.90(4H, m), 3.03(2H, t, J=5.7 Hz), 3.5(1H, m), 3.84(3H, s),4.25(2H, t, J=5.7 Hz), 6.78˜7.85(7H, m).

MS(m/z):477(M⁺), 84.

EXAMPLE 15

[6-Methoxy-2-(3-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.88(3H, d, J=5.3 Hz), 0.94˜2.33(15H, m),2.48˜2.59(4H, m), 2.81 (2H, t, J=5.9 Hz), 3.1 (1H, m), 3.84(3H, s),4.19(2H, t, J=5.9 Hz), 6.77˜7.85(7H, m).

MS(m/z):491(M⁺), 98.

EXAMPLE 16

[6-Methoxy-2-(3-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-homopiperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.88(3H, d, J=5.5 Hz), 1.00˜2.80(17H, m),2.86˜3.00(4H, m), 3.08(2H, t, J=5.7 Hz), 3.84(3H, s), 4.23(2H, t, J=5.7Hz), 6.78˜7.85(7H, m).

MS(m/z):505(M⁺), 112.

EXAMPLE 17

[6-Methoxy-2-(3-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-[1-(3-methylpiperidinyl)]ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.71˜0.99(6H, m), 1.00˜2.67(16H, m), 2.72˜3.15 (5H,m), 3.84(3H, s), 4. 17(2H, t, J=6 Hz), 6.77˜7.85(7H, m).

MS(m/z):505(M⁺), 112.

EXAMPLE 18

(6-Methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.25˜2.62(22H, m), 3.3(1H, m), 3.84(3H, s), 4.08 (2H,t, J=6.3 Hz), 6.79˜7.87(7H, m).

MS(m/z):477(M⁺), 98.

EXAMPLE 19

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(diethylamino)propoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.26(6H, t), 1.40˜2.36(14H, m), 2.78˜3.14(4H, m),3.84(3H, s), 4.13(2H, t, J=5.8 Hz), 6.77˜7.85(7H, m).

MS(m/z):479(M⁺), 86.

EXAMPLE 20

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-pyrrolidinyl)propoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.15˜3.04(23H, m), 3.84(3H, s), 4.11(2H, t, J=6.3 Hz),6.77˜7.85(7H, m).

MS(m/z):477(M⁺), 84.

EXAMPLE 21

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propoxy]phenyl]methanone

¹ H-NMR(CDCl₃. δ):1.12˜3.04(18H, m), 2.47(6H, m). 3.0(1H, m), 3.84 (3H,s), 4.09(2H, t, J=6.2 Hz), 6.77˜7.88(7H, m).

MS(m/z):491(M⁺), 98.

EXAMPLE 22

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-homopiperidinyl)propoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.11˜3.11(20H, m), 2.85(6H, m), 3.84(3H, s), 4.11 (2H,t, J=6.2 Hz), 6.78˜7.85(7H, m).

MS(m/z):505(M⁺), 112.

EXAMPLE 23

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-[1-(3-methylpiperidinyl)]propoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.87(3H, d, J=5.7 Hz), 1.00˜3.13(24H, m), 3.84(3H, s),4.09(2H, t, J=6.3 Hz), 6.77˜7.85(7H, m).

MS(m/z):505(M⁺), 112.

EXAMPLE 24

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-[1-(4-methylpiperazinyl)]propoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.12˜2.29(12H, m), 2.34(3H, s), 2.56(10H, m), 3.84(3H, s), 4.09(2H, t, J=6.3 Hz), 6.77˜7.88(7H, m).

MS(m/z):506(M⁺), 113.

EXAMPLE 25

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-[2-(1,2,3,4-tetrahydroisoquinolinyl)]propoxyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.18˜3.67(21H, m), 3.84(3H, s), 4.15(2H, t, J=6.3 Hz),6.74˜8.45(11H, m).

MS(m/z):539(M⁺), 146.

EXAMPLE 26

(6-Methoxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[3-(1-pyrrolidinyl)propoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.26˜3.77(25H, m), 3.84(3H, s), 4.10(2H, t, J=6.3 Hz),6.78-7.88(7H, m).

MS(m/z):491(M⁺), 84.

EXAMPLE 27

(6-Methoxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.26˜3.77(27H, m), 3.84(3H, s), 4.08(2H, t, J=6.3 Hz),6.76˜7.88(7H, m).

MS(m/z):505(M⁺), 98.

EXAMPLE 28

(6-Methoxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[3-(1-homopiperidinyl)propoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.18˜3.80(29H, m), 3.84(3H, s), 4.10(2H, t, J=6.3 Hz),6.78˜7.92(7H, m).

MS(m/z):519(M⁺), 112.

EXAMPLE 29

(6-Methoxy-2-cyclododecylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.25˜1.85(28H, m), 2.62(4H, t, J=5.3 Hz), 2.88(2H, t,J=5.9 Hz), 3.00˜3.25(1H, m), 3.76(3H, s), 4.23(2H, t, J=5.9Hz),6.84˜7.57(5H, m), 7.79(2H, d, J=8.8 Hz).

MS(m/z):561(M⁺), 459, 98.

EXAMPLE 30

(6-Methoxy-2-isopropylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.30(6H, d, J=6.8 Hz), 1.50˜1.75(6H, m), 2.57(4H, t,J=7.3 Hz), 2.82(2H, t, J=4.2 Hz), 3.31 (1H, m), 4.06(3H, s), 4.19(2H, t,J=5.9 Hz), 6.76˜7.24 (5H, m), 7.80(2H, d, J=9.0 Hz).

MS(m/z):437(M⁺), 98.

EXAMPLE 31

(6-Methoxy-2-isopropylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.30(6H, d, J=6.8 Hz), 1.88˜2.05(4H, m), 3.00(21H, t,J=5.7 Hz), 3.18(2H, t, J=5.7 Hz), 3.34˜3.60(1H, m), 3.84(3H, s),4.38(2H, t, J=5.3 Hz), 6.79˜7.28(5H, m), 7.82(2H, d, J=8.8 Hz).

MS(m/z):423(M⁺), 84.

EXAMPLE 32

48 mg of sodium hydride was added to a THF solution of 0.2 ml ofpyrrolidine, followed by stirring at room temperature for 1 hour. 54 mgof(6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-(2-chloroethoxy)phenyl]methanonewas added, followed by reflux with heating for 10 hours. Water wasadded, the mixture was extracted with ethyl acetate, and the extract waspurified by TLC (developing solvent, chloroform:methanol=9:1) to obtain12 mg of(6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone.

¹ H-NMR(CDCl₃, δ):1.15˜2.10(14H, m), 2.67˜2.86(4H, m), 3.00(2H, t, J=5.7Hz), 3.4(1H, m), 3.84(3H, s), 4.23(2H, t, J=5.7 Hz), 6.78˜7.86(7H, m).

MS(m/z):463(M⁺), 84.

The following compounds of Examples 33 and 34 were synthesized in thesame manner as in Example 32.

EXAMPLE 33

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-homopiperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.83˜2.11(18H, m), 2.74˜2.95(4H, m), 3.04(2H, t, J=6Hz), 3.84(3H, s), 4.20(2H, t, J=6 Hz), 6.78˜7.88(7H, m).

MS(m/z):491(M⁺), 112.

EXAMPLE 34

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(N-morpholinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.85˜2.17(10H, m), 2.56˜2.66(4H, m), 2.85(2H, t, J=5.7Hz), 3.0(1H, m), 3.61˜3.80(4H, m), 3.84(3H, s), 4.20(2H, t, J=5.7 Hz),6.77˜7.89(7H, m).

MS(m/z):479(M⁺), 100.

EXAMPLE 35

50 mg of(6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-(2-chloroethoxy)phenyl]methanonewas dissolved in 5 ml of DMF, 20 mg of potassium iodide and 0.5 ml of3-methylpiperidine were added, and the mixture was stirred at about 40°C. for 8 hours, at room temperature for 2 days and then at about 50° C.for 2 hours. The reaction mixture was concentrated under reducedpressure, a saturated aqueous sodium bicarbonate solution was added, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated saline and then dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue was purified byTLC (developing solvent, chloroform) to obtain 31 mg of(6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-[1-(3methylpiperidinyl)]ethoxy]phenyl]methanone.

¹ H-NMR(CDCl₃, δ):0.87(3H, d, J=5.7 Hz), 1.01˜2.76(17H, m),2.73˜3.11(5H, m), 3.84(3H, s), 4.18(2H, t, J=6 Hz), 6.75˜7.88(7H, m).

MS(m/z):491(M⁺), 112.

The following compound of Example 36 was synthesized in the same manneras in Example 35.

EXAMPLE 36

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(N-morpholinyl)propoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.13˜3.04(18H, m), 3.0(1H, m), 3.73(4H, m), 3.84 (3H,s), 4.10(2H, t, J=4.7 Hz), 6.77˜7.85(7H, m).

MS(m/z):493(M⁺), 100.

EXAMPLE 37

The same operations as in Preparation example 6 were carried out using200 mg of 4-[2-(dimethylamino)ethoxy]benzoic acid in place of4-(2-chloroethoxy)benzoic acid and 45 mg of6-methoxy-2-cyclopentylbenzo[b]thiophene in place of6-methoxy-2-cyclohexylbenzo[b]thiophene, and then purification wascarried out by TLC (developing solvent, chloroform:methanol=19:1) toobtain 35 mg of(6-methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(dimethylamino)ethoxy]phenyl]methanone.

¹ H-NMR(CDCl₃, δ):1.26˜2.29(8H, m), 2.36(6H, s), 2.77(2H, t, J=5.7 Hz),3.25˜3.79(1H, m), 3.84(3H, s), 4.14(2H, t, J=5.7 Hz), 6.79˜7.90(7H, m).

MS(m/z):423(M⁺), 58.

The following compounds of Examples 38 to 58 were synthesized in thesame manner as in Example 37.

EXAMPLE 38

(6-Methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(diethylamino)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.10(6H, t, J=7.2 Hz), 1.26˜2.47(8H, m), 2.70(4H, q),2.94(2H, t, J=6 Hz), 3.25˜3.58(1H, m), 3.84(3H, s), 4.15(2H, t, J=6 Hz),6.79˜7.87(7H, m).

MS(m/z):451(M⁺), 86.

EXAMPLE 39

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(dimethylamino)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.18˜2.12(10H, m), 2.37(6H, s), 2.6˜3.2(3H, m),3.84(3H, s), 4.16(2H, t, J=5.7 Hz), 6.78˜7.85(7H, m).

MS(m/z):437(M⁺), 58.

EXAMPLE 40

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.15˜2.09(10H, m), 2.55˜2.66(4H, m), 2.87(2H, t, J=5.8Hz), 3.0(1H, m), 3.84(3H, s), 4.22(2H, t, J=5.8 Hz), 6.78˜7.85(7H, m).

MS(m/z):477(M⁺), 98.

EXAMPLE 41

(6-Methoxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(dimethylamino)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.26˜2.16(12H, m), 2.38(6H, s), 2.80(2H, t, J=5.6 Hz),2.89˜3.73(1H, m), 3.83(3H, s), 4.16(2H, t, J=5.6 Hz), 6.78˜7.85(7H, m).

MS(m/z):451(M⁺) , 58.

EXAMPLE 42

(6-Methoxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(diethylamino)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.15(6H, t, J=7.2 Hz), 1.26˜2.16(12H, m), 2.78(4H, q),3.01(2H, t, J=5.9 Hz), 3.84(3H, s), 4.23(2H, t, J=5.9 Hz), 6.78˜7.85(7H, m).

MS(m/z):479(M⁺), 86.

EXAMPLE 43

(6-Methoxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.25˜2.22(18H, m), 3.02˜3.31(7H, m), 3.84(3H, s),4.49˜4.60(2H, m), 6.78˜7.86(7H, m).

MS(m/z):491(M⁺), 98.

EXAMPLE 44

[6-Methoxy-2-(3-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(dimethylamino)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.85(3H, t, J=6 Hz), 0.94˜2.31(9H, m), 2.37(6H, s),2.78(2H, t, J=5.6 Hz), 3.84(3H, s), 4.15(2H, t, J=5.6 Hz), 6.77˜7.85(7H,m).

MS(m/z):451(M⁺), 58.

EXAMPLE 45

[6-Methoxy-2-(3-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(diethylamino)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.87(6H, t), 1.00˜2.17(12H, m), 3.22(4H, q), 3.42 (2H,t, J=4.7 Hz), 3.6(1H, m), 3.85(3H, s), 4.60(2H, t, J=4.7 Hz),6.78˜7.87(7H, m).

MS(m/z):479(M⁺), 86.

EXAMPLE 46

[6-Methoxy-2-(4-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.97(3H, t, J=7.2 Hz), 1.22˜2.08(15H, m),2.51˜2.69(4H, m), 2.84(2H, t, J=5.9 Hz), 3.0(1H, m), 3.84(3H, s),4.21(2H, t, J=5.9 Hz), 6.78˜7.88(7H, m).

MS(m/z):491(M⁺), 98.

EXAMPLE 47

[6-Methoxy-2-(1-cyclooctenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.97˜2.59(19H, m), 2.65˜2.78(4H, m), 2.93(2H, br t),3.79(3H, s), 4.25(2H, br t), 6.74˜8.05(7H, m).

MS(m/z):503(M⁺), 98.

EXAMPLE 48

(6-Methoxy-2-methylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.85˜2.00(4H, m), 2.43(3H, s), 2.86˜3.05(4H, m),3.18(2H, t, J=5.4 Hz), 3.84(3H, s), 4.29(2H, t, J=5.4 Hz), 6.81˜7.85(7H,m).

MS(m/z):395(M⁺), 84.

EXAMPLE 49

(6-Methoxy-2-chlorobenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.83˜1.98(4H, m), 2.84˜2.91(4H, m), 3.15(2H, t, J=5.4Hz), 3.75(3H, s), 4.26(2H, t, J=5.4 Hz), 6.94˜7.86(7H, m).

MS(m/z):417, 415.

EXAMPLE 50

(2-Cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.09˜2.22(16H, m), 2.64˜2.76(4H, m), 2.95(2H, t, J=5.7Hz), 3.0(1H, m), 4.30(2H, t, J=5.7 Hz), 6.83˜7.89(8H, m).

MS(m/z):447(M⁺), 98.

EXAMPLE 51

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinylcarbonyl)ethyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.14˜2.20(16H, m), 2.61˜2.74(2H, m), 2.91˜3.13 (2H,m), 3.35˜3.67(4H, m), 3.84(3H, s), 6.77˜7.92(7H, m).

MS(m/z):489(M⁺), 363, 349.

EXAMPLE 52

(6-Methoxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(1-piperidinylcarbonyl)ethyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.26˜2.06(18H, m), 2.55˜2.71(2H, m), 2.94˜3.14 (2H,m), 3.30˜3.61(4H, m), 3.84(3H, s), 6.77˜7.80(7H, m).

MS(m/z):503(M⁺).

EXAMPLE 53

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(dimethylcarbamoyl)ethyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.10˜2.17(10H, m), 2.54˜2.78(2H, m), 2.95(6H, s),2.95˜3.30(2H, m), 3.84(3H, s), 6.77˜7.95(7H, m).

MS(m/z):449(M⁺), 362.

EXAMPLE 54

(6-Methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.30˜2.90(18H, m), 2.97(2H, t, J=6 Hz), 3.35(1H, m),3.85(3H, s), 4.32(2H, t, J=6 Hz), 6.80˜7.40(5H, m), 7.84(2H, d, J=8.8Hz).

MS(m/z):463(M⁺), 352, 98.

EXAMPLE 55

[6-Methoxy-2-(4-oxocyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.30˜2.80(18H, m), 2.87(2H, t, J=6 Hz), 3.50(1H, m),3.85(3H, s), 4.24(2H, t, J=6 Hz), 6.70˜7.30(5H, m), 7.81(2H, d, J=9 Hz).

MS(m/z):491(M⁺), 380, 98.

EXAMPLE 56

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinylcarbonyl)ethyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.18˜2.05(14H, m), 2.57(2H, t, J=7.7 Hz), 3.08(2H, t,J=7.9 Hz), 2.80˜3.60(1H, m), 3.20˜3.60(4H, m), 3.84(3H, s), 6.83(1H, dd,J=8.8, 2.4 Hz), 7.15˜7.42(4H, m), 7.75(2H, d, J=8.4 Hz).

MS(m/z):475(M⁺).

EXAMPLE 57

[6-Methoxy-2-(2-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-pyrrolidinylcarbonyl)ethyl]phenyl]methanone

¹ -NMR(CDCl₃, δ):0.84(3H, d, J=7.3 Hz), 1.25˜2.10(13H, m), 2.57(2H, t,J=7.5 Hz), 3.07(2H, t, J=7.5 Hz), 2.90˜3.60(5H, m), 3.84(3H, s),6.82(1H, dd, J=8.8, 2.4 Hz), 7.11˜7.35(4H, m), 7.73(2H, d, J=8.4 Hz).

MS(m/z):489(M⁺).

EXAMPLE 58

(6-Methoxy-2-cycloheptylbenzo[b]thien-3-yl )[4-2-(1-pyrrolidinylcarbonyl)ethyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.26˜2.15(16H, m), 2.58(2H, t, J=7.9 Hz), 3.08(2H, t,J=7.9 Hz), 2.90˜3.60(1H, m). 3.20˜3.53(4H, m), 3.84(3H, s), 6.84(1H, dd,J=8.8, 2.4 Hz), 7.20˜7.34(4H, m), 7.75(2H, d, J=8.4 Hz).

MS(m/z):489(M⁺), 273, 72.

EXAMPLE 59

88 mg of chromium trioxide was added to 5 ml of pyridine to give ayellow gruel-like solution, a pyridine solution of 105 mg of(6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propyl]phenyl]methanolwas added, and the mixture was stirred at room temperature for 1 hour.After addition of ice to the reaction mixture, the mixture was extractedwith ethyl acetate and the organic layer was dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the resultantcrude product was purified by TLC (developing solvent,chloroform:methanol=19:1) to obtain 47 mg of(6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propyl]phenyl]methanone.

¹ H-NMR(CDCl₃, δ):1.15˜2.09(16H, m), 2.30˜2.57(6H, m), 2.62˜2.96 (4H,m), 3.84(3H, s), 6.78˜7.79(7H, m).

MS(m/z):475(M⁺), 98.

The following compounds of Examples 60 to 63 were synthesized in thesame manner as in Example 59.

EXAMPLE 60

(6-Methoxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.13˜2.19(18H, m), 2.40˜3.29(10H, m), 3.85(3H, s),6.78˜7.79(7H, m).

MS(m/z):489(M⁺), 98.

EXAMPLE 61

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(dimethylamino)propyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.05˜2.16(12H, m), 2.35(6H, s), 2.35˜2.98(4H, m),3.85(3H, s), 6.78˜7.82(7H, m).

MS(m/z):435(M⁺), 58.

EXAMPLE 62

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-pyrrolidinyl)propyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.18˜2.07(16H, m), 2.54˜3.15(9H, m), 3.84(3H, s),6.78˜7.80(7H, m).

MS(m/z):461(M⁺), 84.

EXAMPLE 63

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[4-(1-pyrrolidinyl)butyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.20˜2.15(18H, m), 2.40˜2.85(8H, m), 2.75˜3.15 (1H,m), 3.84(3H, s), 6.83(1H, dd, J=8.8, 2.4 Hz), 7.17˜7.40(4H, m), 7.74(2H,d, J=8.1 Hz).

MS(m/z):475(M⁺), 84.

EXAMPLE 64

50 mg of[6-methoxy-2-(4-oxocyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanonewas dissolved in 4 ml of methanol and 0.5 ml of THF, followed by icecooling, 6 mg of sodium borohydride was added, and the mixture wasstirred at 0° C. for 15 minutes. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and dried over anhydrous sodium sulfate, andthen the solvent was distilled off. The resultant crude product waspurified by TLC (developing solvent, chloroform:methanol=19:1) to obtain32 mg of[6-methoxy-2-(4-hydroxycyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone.

¹ H-NMR(CDCl₃, δ):1.10˜2.20(14H, m), 2.60˜3.00(4H, m), 3.06(2H, t, J=6Hz), 3. 60(2H, m), 3.85(3H, s), 4.41(2H, t, J=6 Hz), 6.70˜7.30(5H, m),7.80 (2H, d, H=9 Hz).

MS(m/z):493(M⁺), 382, 323, 98.

EXAMPLE 65

200 mg of aluminum chloride was added to 20 ml of dichloromethane, andwhile the mixture was stirred at 0° C., 10 ml of a dichloromethanesolution of 0.3 ml of oxalyl chloride was added dropwise and the mixturewas stirred at 0° C. for 10 minutes. 2 ml of a dichloromethane solutionof 100 mg of 4-phenylbutyrylpyrrolidine was added dropwise, and themixture was stirred at room temperature for 30 minutes. Water was added,the mixture was extracted with dichloromethane, and the organic layerwas dried over anhydrous magnesium sulfate and then concentrated. Theresidue was dissolved in 20 ml of dichloromethane, 100 mg of6-methoxy-2-cyclohexylbenzo[b]thiophene and 200 mg of aluminum chloridewere added, and the mixture was stirred at room temperature for 2 hours.1 ml of THF, 0.3 ml of 20% hydrochloric acid and 1 ml of water wereadded to the reaction mixture at 25° C. or less, a saturated aqueoussodium bicarbonate solution was added to make the mixture alkaline, andthe mixture was extracted with dichloromethane. The organic layer wasdried over anhydrous magnesium sulfate, the solvent was distilled off,and the resultant crude product was purified by TLC (developing solvent,ethyl acetate:n-hexane=1:5) to obtain 54 mg of(6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-pyrrolidinylcarbonyl)propyl]phenyl]methanone.

MS(m/z):489(M⁺), 113.

The following compounds of Examples 66-68 were synthesized in the samemanner as in Example 65.

EXAMPLE 66

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-piperidinylcarbonyl)propyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.17˜1.86(16H, m), 1.91˜2.15(2H, m), 2.34(2H, t, J=6.8Hz), 2.76(2H, t, J=7.5 Hz), 3.20˜3.65(5H, m), 3.84(3H, s), 6.83(1H, dd,J=9.0, 2.4 Hz), 7.18˜7.30(4H, m), 7.75(2H, d, J=8.4 Hz).

MS(m/z):503(M⁺), 127.

EXAMPLE 67

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-4-(1-piperidinyl)butyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.25˜2.05(20H, m), 2.24˜2.39(6H, m), 2.69(2H, t, J=7.0Hz), 2.80˜3.10(1H, m), 3.84(3H, s), 6.84(1H, dd, J=9.0, 2.4 Hz),7.13˜7.27(5H, m), 7.74(2H, d, J=8.4 Hz).

MS(m/z):489(M⁺), 98.

EXAMPLE 68

(6-Methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(dimethylcarbamoyl)propyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.15˜1.85(12H, m), 1.90˜2.20(2H, m), 2.33(2H, t, J=6.8Hz), 2.76(2H, t, J=7.7 Hz), 2.95(6H, s), 3.85(3H, s), 6.77˜7.80(7H, m).

MS(m/z):463(M⁺), 87.

EXAMPLE 69

35 mg of(6-methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(dimethylamino)ethoxy]phenyl]methanonewas dissolved in 5 ml of dichloromethane, 65 mg of aluminum chloride and0.03 ml of ethanethiol were added, and the mixture was stirred at roomtemperature for 2 hours. 0.3 ml of THF, 0.075 ml of 20% hydrochloricacid and 0.3 ml of water were added to the reaction mixture, a saturatedaqueous sodium bicarbonate solution was added to make the mixturealkaline, and the resultant mixture was extracted with ethyl acetate.The organic layer was dried over anhydrous magnesium sulfate, thesolvent was distilled off, and the resultant crude product was purifiedby TLC (developing solvent, chloroform:methanol=19:1) to obtain 21 mg of(6-hydroxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(dimethylamino)ethoxy]phenyl]methanone.

¹ H-NMR(CD₃ OD, δ):1.24˜2.27(8H, m), 2.37(6H, s), 2.81(2H, t, J=5.5 Hz),4.18(2H, t, J=5.5 Hz), 6.68˜7.87(7H, m).

MS(m/z):409(M⁺), 58.

The following compounds of Examples 70 to 132 were synthesized in thesame manner as in Example 69.

EXAMPLE 70

(6-Hydroxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(diethylamino)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.06(6H, t, J=7.2 Hz), 1.20˜2.21 (8H, m), 2.64(4H,q), 2.89(2H, t, J=5.7 Hz), 4.12(2H, t, J=5.7 Hz), 6.68˜7.84(7H, m).

MS(m/z):437(M⁺), 86.

EXAMPLE 71

(6-Hydroxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.23˜2.15(12H, m), 2.62˜2.79(4H, m), 2.99(2H, t,J=5.5 Hz), 4.22(2H, t, J=5.5 Hz), 6.69˜7.84(7H, m).

MS(m/z):435(M⁺), 84.

EXAMPLE 72

(6-Hydroxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(1-homopiperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.26˜2.15(16H, m), 2.83˜2.91(4H, m), 3.05(2H, t,J=5.6 Hz), 4.22(2H, t, J=5.6 Hz), 6.68˜7.84(7H, m).

MS(m/z):463(M⁺), 112.

EXAMPLE 73

(6-Hydroxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-[1-(3-methylpiperidinyl)]ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.89(3H, d, J=5.7 Hz), 1.29˜2.15(15H, m),2.81˜3.04(5H, m), 4.24(2H, t, J=5.6 Hz), 6.69˜7.84(7H, m).

MS(m/z):463(M⁺), 112.

EXAMPLE 74

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(dimethylamino)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.09˜2.29(10H, m), 2.36(6H, s), 2.81(2H, t, J=5.5Hz), 4.19(2H, t, J=5.5 Hz), 6.68˜7.83(7H, m).

MS(m/z):423(M⁺), 58.

EXAMPLE 75

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(diethylamino)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.11(6H, t, J=7.2 Hz), 1.22˜1.94(10H, m), 2.72(4H,q), 2.98(2H, t, J=5.6 Hz), 4.21 (2H, t, J=5.6 Hz), 6.69˜7.8.3(7H, m).

MS(m/z):451(M⁺), 86.

EXAMPLE 76

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.11˜2.03(14H, m), 2.78˜2.99(4H, m), 3.10(2H, t,J=5.4 Hz), 4.27 (2H, t, J=5.4 Hz), 6.68˜7.86(7H, m).

MS(m/z):449(M⁺), 84.

EXAMPLE 77

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.15˜2.14(16H, m), 2.50˜2.61(4H, m), 2.80(2H, t,J=5.5 Hz), 3.0(1H, m), 4.18(2H, t, J=5.5 Hz), 6.67˜7.80(7H, m).

MS(m/z):463(M⁺), 98.

EXAMPLE 78

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-homopiperidinyl)ethoxy]phenyl]methanone

MS(m/z):477(M⁺), 112.

EXAMPLE 79

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-[1-(3-methylpiperidinyl)]ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.87(3H, d, J=5.7 Hz), 1.01˜2.26(17H, m),2.73˜3.12(5H, m), 4.20(2H, t, J=5.6 Hz), 6.68˜7.84(7H, m).

MS(m/z):477(M⁺), 112.

EXAMPLE 80

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(N-morpholinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.89˜2.06(10H, m), 2.59(4H, br t), 2.82(2H, t, J=5.5Hz), 3.70(4H, br t), 4.23(2H, t, J=5.5 Hz), 6.69˜7.85(7H, m).

MS(m/z):465(M⁺), 100.

EXAMPLE 81

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-[1-(4-methylpiperazinyl)]ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.89˜2.08(10H, m), 2.58(3H, s), 2.61˜3.00(10H, m),4.23(2H, t, J=5.4 Hz), 6.68˜7.83(7H, m).

MS(m/z):478(M⁺), 113.

EXAMPLE 82

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-[2-(1,2,3,4-tetrahydroisoquinolinyl)]ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.08˜2.17(10H, m), 2.80˜3.04(9H, m), 3.75(2H, s),4.28(2H, t, J=5.6 Hz), 6.68˜7.82(11H, m).

MS(m/z):511(M⁺), 146.

EXAMPLE 83

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-[1-(4-hydroxypiperidinyl)]ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.08˜3.08(21H, m), 3.56˜3.70(1H, m), 4.22(2H, t,J=5.5 Hz), 6.69˜7.86(7H, m).

MS(m/z):479(M⁺), 114.

EXAMPLE 84

(6-Hydroxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(dimethylamino)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.28˜2.15(12H, m), 2.39(6H, s), 2.85(2H, t, J=5.5Hz), 4.20(2H, t, J=5.5 Hz), 6.68˜7.83(7H, m).

MS(m/z):437(M⁺), 58.

EXAMPLE 85

(6-Hydroxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(diethylamino)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.11(6H, t, J=7.2 Hz), 1.22˜1.93(12H, m), 2.71(4H,q), 2.97 (2H, t, J=5.6 Hz), 4.20(2H, t, J=5.6 Hz), 6.79˜7.83(7H, m).

MS(m/z):465(M⁺), 86.

EXAMPLE 86

(6-Hydroxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.17˜2.07(16H, m), 2.71˜2.99(4H, m), 3.08(2H, t,J=5.5 Hz), 4.26(2H, t, J=5.5 Hz), 6.69˜7.86(7H, m).

MS(m/z):463(M⁺), 84.

EXAMPLE 87

(6-Hydroxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.24˜2.07(18H, m), 2.53˜2.68(4H, m), 2.83(2H, t,J=5.6 Hz), 4.23(2H, t, J=5.6 Hz), 6.69˜7.83(7H, m).

MS(m/z):477(M⁺), 98.

EXAMPLE 88

(6-Hydroxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(1-homopiperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.17˜2.17(20H, m), 2.75˜2.95(4H, m), 3.05(2H, t,J=5.6 Hz), 4.22(2H, t, H=5.6 Hz), 6.68˜7.85(7H, m).

MS(m/z):491(M⁺), 112.

EXAMPLE 89

(6-Hydroxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-[1-(3-methylpiperidinyl)]ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.83(3H, d, J=5.7 Hz), 1.53˜2.06(18H, m),2.77˜3.08(5H, m), 4.21(2H, t, J=5.6 Hz), 6.67˜7.82(7H, m).

MS(m/z):491(M⁺), 112.

EXAMPLE 90

[6-Hydroxy-2-(2-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.83(3H, d, J=7.0 Hz), 1.28˜2.05(13H, m),2.68˜2.86(4H, m), 3.01(2H, t, J=5.5 Hz), 4.24(2H, t, J=5.5 Hz),6.69˜7.84(7H, m).

MS(m/z):463(M⁺), 84.

EXAMPLE 91

[6-Hydroxy-2-(2-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.83(3H, d, J=7.0 Hz), 1.23˜2.15(15H, m),2.60˜2.71(4H, m), 2.90(2H, t, J=5.5 Hz), 4.24(2H, t, J=5.5 Hz),6.68˜7.83(7H, m).

MS(m/z):477(M⁺), 98.

EXAMPLE 92

[6-Hydroxy-2-(2-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-homopiperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.84(3H, d, J=7.0 Hz), 1.12˜2.03(17H, m),2.85˜2.95(4H, m), 3.07(2H, t, J=5.7 Hz), 4.24(2H, t, J=5.7 Hz),6.69˜7.84(7H, m).

MS(m/z):491(M⁺), 112.

EXAMPLE 93

[6-Hydroxy-2-(3-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(dimethylamino)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.87(3H, d, J=6.6 Hz), 1.03˜2.00(9H, m), 2.39(6H, s),2.85(2H, t, J=5.5 Hz), 4.20(2H, t, J=5.5 Hz), 6.68˜7.83(7H, m).

MS(m/z):437(M⁺), 58.

EXAMPLE 94

[6-Hydroxy-2-(3-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(diethylamino)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.88(3H, d, J=7.0 Hz), 1.18(6H, t), 1.26˜2.15(9H, m),2.82(4H, q), 3.08(2H, t, J=5.5 Hz), 4.24(2H, t, J=5.5 Hz), 6.69˜7.89(7H,m).

MS(m/z):465(M⁺), 86.

EXAMPLE 95

[6-Hydroxy-2-(3-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.88(3H, d, J=5.5 Hz), 1.17˜1.96(13H, m),2.76˜2.89(4H, m), 3.08(2H, t, J=5.4 Hz), 4.26(2H, t, J=5.4 Hz),6.78˜7.84(7H, m).

MS(m/z):463(M⁺), 84.

EXAMPLE 96

[6-Hydroxy-2-(3-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.88(3H, d, J=5.9 Hz), 1.16˜2.03(21H, m), 3.58(2H, t,J=4.6 Hz), 4.49(2H, t, J=4.6 Hz), 6.77˜7.86(7H, m).

MS(m/z):477(M⁺), 98.

EXAMPLE 97

[6-Hydroxy-2-(3-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-homopiperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.88(3H, d, J=5.5 Hz), 1.03˜1.91(17H, m),2.89˜3.02(4H, m), 3.11(2H, t, J=5.5 Hz), 4.25(2H, t, J=5.5 Hz),6.69˜7.83(7H, m).

MS(m/z):491(M⁺), 112.

EXAMPLE 98

[6-Hydroxy-2-(3-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-[1-(3-methylpiperidinyl)]ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.84˜1.00(6H, m), 1.00˜3.20(20H, m), 4.30(2H, t,J=5.5 Hz), 6.68˜7.83(7H, m).

MS(m/z):4.91(M⁺), 112.

EXAMPLE 99

[6-Hydroxy-2-(4-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.94(3H, d, J=7.7 Hz), 1.02˜1.94(9H, m),2.59˜2.75(4H, m), 2.89(2H, t, J=5.5 Hz), 4.25(2H, t, J=5.5 Hz),6.69˜7.86(7H, m).

MS(m/z):477(M⁺), 98.

EXAMPLE 100

[6-Hydroxy-2-(1-cyclooctenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):0.84˜1.88(19H, m), 2.57˜2.84(6H, m), 4.18(2H, t),6.77˜7.94(7H, m).

MS(m/z):489(M⁺), 98.

EXAMPLE 101

(6-Hydroxy-2-methylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.77˜1.99(4H, m), 2.40(3H, s), 2.62˜2.82(4H, m),2.96(2H, t, J=5.5 Hz), 4.23(2H, t, J=5.5 Hz), 6.71˜7.87(7H, m).

MS(m/z):381(M⁺), 84.

EXAMPLE 102

(6-Hydroxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.25˜2.17(16H, m), 2.46˜2.66(6H, m), 4.09(2H, t, J=6Hz), 6.68˜7.82(7H, m).

EXAMPLE 103

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(diethylamino)propoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.07˜2.13(18H, m), 2.68˜2.97(7H, m), 4.15(2H, t,J=5.9 Hz), 6.71˜7.83(7H, m).

MS(m/z):465(M⁺), 86.

EXAMPLE 104

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-pyrrolidinyl)propoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.11˜2. 22(16H, m), 2.67˜3.06(7H, m), 4.13(2H, t,J=5.81 Hz), 6.68˜7.85(7H, m).

MS(m/z):463(M⁺), 84.

EXAMPLE 105

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.16˜2.13(18H, m), 2.58˜2.89(7H, m), 4.11(2H, t, J=6Hz), 6.68˜7.81 (7H, m).

MS(m/z):477(M⁺), 98.

EXAMPLE 106

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-homopiperidinyl)propoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.17˜3.38(27H, m), 4.20(2H, t, J=5.6 Hz),6.78˜7.83(7H, m).

MS(m/z):491(M⁺), 112.

EXAMPLE 107

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-[1-(3-methylpiperidinyl) ]propoxy]phenyl]methanone

¹ -NMR(CD₃ OD, δ):0.95(3H, d, J=5.9 Hz), 1.06˜3.34(24H, m), 4.15(2H, t,J=5.81 Hz), 6.68˜7.82(7H, m).

MS(m/z):491(M⁺), 112.

EXAMPLE 108

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(N-morpholinyl)propoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.09˜2.13(12H, m), 2.43˜2.91(7H, m), 3.69(4H, br t),4.12(2H, t, J=6 Hz), 6.68∫7.84(7H, m).

MS(m/z):479(M⁺), 100.

EXAMPLE 109

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-[1-(4-methylpiperazinyl)]propoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.14˜2.10(12H, m), 2.52(3H, s), 2.57˜2.90(11H, m),4.17(2H, t, J=6 Hz), 6.78˜7.82(7H, m).

MS(m/z):492(M⁺), 113.

EXAMPLE 110

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-[2-(1,2,3,4-tetrahydroisoquinolinyl)]propoxy]phenyl]methanone

MS (m/z):525(M⁺), 146.

EXAMPLE 111

(6-Hydroxy-2-cycloheptylbenzo[b]thien-3-yl)[4-3-(1-pyrrolidinyl)propoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.25˜2.24(18H, m), 2.51˜3.16(7H, m), 4.11(2H, t,J=5.9 Hz), 6.68˜7.84 (7H, m).

MS(m/z):477(M⁺), 84.

EXAMPLE 112

(6-Hydroxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.17˜2.17(20H, m), 2.42˜2.75(7H, m), 4.09(2H, t,J=5.9 Hz), 6.68˜7.83(7H, m).

MS(m/z):491(M⁺), 98.

EXAMPLE 113

(6-Hydroxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[3-(1-homopiperidinyl)propoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.24˜2.17(22H, m), 2.71˜3.00(7H, m), 4.11(2H, t,J=5.9 Hz), 6.67˜7.81 (7H, m).

MS(m/z):505(M⁺), 112.

EXAMPLE 114

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinylcarbonyl)ethyl]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.15˜1.94(16H, m), 2.73˜3.03(4H, m), 3.27˜3.64 (4H,m), 6.68˜7.77(7H, m).

MS(m/z):475(M⁺), 348, 335.

EXAMPLE 115

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.10˜2.17(16H, m), 2.33˜2.98(10H, m), 6.64˜7.74(7H,m).

MS(m/z):461(M⁺), 98.

EXAMPLE 116

(6-Hydroxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(1-piperidinylcarbonyl)ethyl]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.11˜2.17(18H, m), 2.56˜2.80(2H, m), 2.92˜3.20 (2H,m), 3.27˜3.60(4H, m), 6.67˜7.75(7H, m).

MS(m/z):489(M⁺), 363,349.

EXAMPLE 117

(6-Hydroxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propyl]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.22˜2.15(18H, m), 2.32˜2.48(4H, m), 2.65˜2.82 (2H,m), 2.96˜3.10(4H, m), 6.69˜7.77(7H, m).

MS(m/z):475(M⁺), 98.

EXAMPLE 118

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(dimethylamino)propyl]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.13˜2.12(12H, m), 2.72˜3.12(4H, m), 2.77(6H, s),6.77˜7.81 (7H, m).

MS(m/z):421(M⁺), 58.

EXAMPLE 119

(6-Hydroxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.30˜2.30(14H, m), 2.60(4H, m), 2.85(2H, t, J=6 Hz),3.30(1H, m), 4.18(2H, t, J=6 Hz), 6.60˜7.30(5H, m), 7.75(2H, d,J=8.8Hz).

MS(m/z):449(M⁺), 98.

EXAMPLE 120

[6-Hydroxy-2-(4-hydroxycyclohexyl)benzo[b]-thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.10˜2.20(14H, m), 2.60˜2.90(4H, m), 2.97(2H, t, J=6Hz), 3.55(2H, m), 4.27(2H, t, J=6 Hz), 6.60˜7.30(5H, m), 7.78(2H, 8.8Hz).

MS(m/z):479(M⁺), 368, 309, 98.

EXAMPLE 121

(6-Hydroxy-2-cyclododecylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.15˜1.85(28H, m), 2.65(4H, t, J=4.8 Hz), 2.92(2H, t,J=5.5 Hz), 3.00˜3.40(1H, m), 4.29(2H, t, J=5.9 Hz), 6.87˜7.86(8H,

MS(m/z):547(M⁺), 98.

EXAMPLE 122

(6-Hydroxy-2-isopropylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.28(6H, d, J=6.8 Hz), 1.45˜1.84(6H, m), 2.61(4H, t,J=2.6 Hz), 2.85(2H, t, J=5.7 Hz), 3.31(1H, m), 4.19(2H, t, J=5.5 Hz),4.5˜5.2(1H, br s), 6.65˜7.24(5H, m), 7.85(2H, d, J=8.8 Hz).

MS(m/z):423(M⁺), 98.

EXAMPLE 123

(6-Hydroxy-2-isopropylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.27(6H, d, J=6.8 Hz), 1.80˜2.05(4H, m), 2.91(4H, t,J=3.0 Hz), 3.11(2H, t, J=5.1Hz), 3.00-3.44(1H, m), 4.27(2H, t, J=5.3Hz), 4.0-4.5(1H, br s), 6.67-7.76(7H, m).

MS(m/z):409(M⁺), 84.

EXAMPLE 124

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinylcarbonyl)ethyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.20˜2.04(14H, m), 2.59(2H, t, J=7.9 Hz), 3.07(2H, t,J=7.9 Hz), 2.80˜3.60(1H, m), 3.25˜3.55(4H, m), 6.72˜7.78(8H, m).

MS(m/z):461(M⁺), 72.

EXAMPLE 125

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-pyrrolidinyl)propyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.10˜2.20(16H, m), 2.60˜3.00(9H, m), 6.69˜7.74 (7H,m).

MS(m/z):447(M⁺), 84.

EXAMPLE 126

[6-Hydroxy-2-(2-methylcyclohexyl)benzo[b]thien-3-yl][4-[2-(1-pyrrolidinylcarbonyl)ethyl)phenyl]methanone

¹ H-NMR(CDCl₃, δ):0.82(3H, d, J=7.0 Hz), 1.10˜2.20(13H, m), 2.59(2H, t,J=7.7 Hz), 2.90˜3.80(1H, m), 3.07(2H, t, J=7.9 Hz), 3.40(4H, t, J=6.6Hz), 6.78(1H, dd, J=8.6, 2.4 Hz), 7.03˜7.31(4H, m), 7.72(2H, d, J=8.4Hz).

MS(m/z):475(M⁺), 72.

EXAMPLE 127

(6-Hydroxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinylcarbonyl)ethyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.20˜2.15(16H, m), 2.59(2H, t, J=7.9 Hz),2.80˜3.70(1H, m), 3.07(2H, t, J=7.5 Hz), 3.20˜3.60(4H, m), 6.77(1H, dd,J=8.8, 2.4 Hz), 7.11˜7.32(5H, m), 7.74 (2H, d, J=8.4 Hz).

MS(m/z):475(M⁺), 259, 72.

EXAMPLE 128

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-pyrrolidinylcarbonyl)propyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.50˜2.17(14H, m), 2.24(2H, t, J=6.4 Hz), 2.74(2H, t,J=7.5 Hz), 3.28˜3.55(5H, m), 6.78(1H, dd, J=8.8, 2.4 Hz), 7.09˜7.26(5H,m), 7.72(2H, d, J=8.4 Hz).

MS(m/z):475(M⁺), 113.

EXAMPLE 129

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[4-(1-pyrrolidinyl)butyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.13˜2.08(18H, m), 2.62˜2.94(8H, m), 3.10˜3.40 (1H,m), 6.73(1H, dd, J=8.6, 2.2 Hz), 6.82˜7.23(5H, m), 7.67(2H, d, J=8.1Hz).

MS(m/z):461(M⁺), 84.

EXAMPLE 130

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-piperidinylcarbonyl)propyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.12˜1.85(16H, m), 1.90˜2.14(2H, m), 2.37(2H, t, J=6.8Hz), 2.74(2H, t, J=7.9 Hz), 3.30˜3.60(5H, m), 6.77(1H, dd, J=8.8, 2.4Hz), 7.10˜7.26(5H, m), 7.73(2H, d, J=8.1 Hz).

MS(m/z):489(M⁺), 127.

EXAMPLE 131

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[4-(1-piperidinyl)butyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.17˜2.03(20H, m), 2.30˜2.75(6H, m), 2.80˜3.20 (1H,m), 3.50˜4.10(2H, m), 6.71(1H, dd, J=8.8, 2.4 Hz), 7.07˜7.22(5H, m),7.70(2H, d, J=8.4 Hz).

MS(m/z):475(M⁺), 98.

EXAMPLE 132

(6-Hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(dimethylcarbamoyl)propyl]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.16˜1.85(12H, m), 1.90˜2.15(2H, m); 2.35(2H, t, J=7.3Hz), 2.75(2H, t, J=7.7 Hz). 2.5˜3.1 (1H, m), 2.96(6H, s), 6.69˜7.79 (8H,m).

MS(m/z):449(M⁺), 87.

EXAMPLE 133

27 mg of(6-hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanonewas dissolved in 1 ml of pyridine, 0.1 ml of benzoyl chloride was added,and the mixture was stirred at room temperature for 1 hour. Afteraddition of ice, the reaction mixture was stirred for 1 hour andextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, the solvent was distilled off, and the resultantcrude product was purified by TLC (developing solvent,chloroform:methanol=9:1) to obtain 37 mg of(6-benzoyloxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone.

¹ H-NMR(CD₃ OD, δ):1.17˜1.96(16H, m), 2.62˜2.73(4H, m), 2.92(2H, t,J=5.6 Hz), 4.25(2H, t, J=5.6 Hz), 6.98˜8.22(12H, m).

MS(m/z):567(M⁺), 98.

The following compounds of Examples 134 to 138 were synthesized in thesame manner as in Example 133.

EXAMPLE 134

(6-Dimethylcarbamoyloxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃ δ):1.13˜2.11(16H, m), 2.54˜2.65(4H, m), 2.86(2H, t, J=5.7Hz), 3.02(6H, s), 4.22(2H, t, J=5.7 Hz), 6.83˜7.88(7H, m).

MS(m/z):534(M⁺), 98, 72.

EXAMPLE 135

(6-Benzoyloxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CD₃ OD, δ):1.17˜2.16(14H, m), 3.27˜3.50(4H, m), 3.59(2H, t),4.43(2H, t), 7.03˜8.24(12H, m).

MS(m/z):553(M⁺), 84.

EXAMPLE 136

(6-Benzoyloxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.17˜2.62(20H, m), 3.02˜3.23(6H, m), 4.12(2H, m),6.71˜8.27(12H, m).

MS(m/z):595(M⁺), 98.

EXAMPLE 137

(6-Benzoyloxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[3-(1-homopiperidinyl)propoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.26˜2.49(22H, m), 3.04˜3.44(6H, m), 4.11(2H, m),6.81˜8.27(12H, m).

MS(m/z):609(M⁺), 112.

EXAMPLE 138

(6-Benzoyloxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[3-(1-pyrrolidinyl)propoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.21˜2.63(18H, m), 3.20˜3.39(4H, m), 4.09˜4.22 (2H,m), 6.83˜8.27(12H, m).

MS(m/z):581(M⁺), 84.

EXAMPLE 139

A mixture of 10 mg of[6-hydroxy-2-(4-hydroxycyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone,0.5 ml of acetic anhydride and 0.5 ml of pyridine was stirred at roomtemperature for 18 hours. After addition of cold water, the reactionmixture was stirred at room temperature for 30 minutes and extractedwith ethyl acetate. The organic layer was washed with water andsaturated aqueous sodium bicarbonate solution, and dried over anhydroussodium sulfate. The solvent was distilled off, and the resultant crudeproduct was purified by TLC (developing solvent,chloroform:methanol=9:1) to obtain 5 mg of[6-acethoxy-2-(4-acetoxycyclohexyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone.

¹ H-NMR(CDCl₃, δ):1.10˜2.20(14H, m), 2.01(3H, s), 2.31(3H, s),2.60˜2.90(4H, m), 3.03(2H, t, J=6 Hz), 4.36(2H, t, J=6 Hz), 4.70(1H, m),6.80˜7.60(5H, m), 7.80(2H, d, J=8.8 Hz).

MS(m/z):563(M⁺), 452, 434, 393, 351, 309, 98.

The following compound of Example 140 was synthesized in the same manneras in Example 139.

EXAMPLE 140

(6-Acetoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

¹ H-NMR(CDCl₃, δ):1.10˜2.20(16H, m), 2.31(3H, s), 2.40˜2.70(4H, m),2.81(2H, t, J=6 Hz), 3.00(1H, m), 4.19(2H, t, J=6 Hz), 6.80˜7.60(5H, m),7.80(2H, d, J=8.8 Hz).

An example of preparation of a drug containing a compound of thisinvention is shown below.

    ______________________________________                                                              mg/tablet                                               ______________________________________                                        Active ingredient        10.0                                                 Starch                   20.0                                                 Lactose                 142.0                                                 Carboxymethylcellulose calcium                                                                         5.0                                                  Talc                     2.0                                                  Magnesium stearate       1.0                                                                          180 mg                                                ______________________________________                                    

The active ingredient is pulverized into a grain size of 70 microns orless, the starch, lactose and carboxymethylcellulose calcium were addedthereto, and the mixture is sufficiently mixed. A 10% starch paste isadded to the mixture and the resultant mixture is stirred and mixed toprepare granules. After drying, the granules are graded so that thegrain size becomes around 1,000 microns, talc and magnesium stearate areadded thereto, and the mixture is tableted.

Industrial Applicability

The compounds of the above formula (I) of this invention have anantiestrogenic activity, and are useful for curing or treatment ofestrogen-dependent diseases such as, for example, breast cancer,endometrial cancer, endometriosis, prostatomegaly and mastopathy.

We claim:
 1. A benzothiophene derivative represented by the followinggeneral formula or a salt thereof ##STR17## wherein R¹ denotes ahydroxyl group, a lower alkoxy group, an acyloxy group or anN,N-di-lower alkyl-substituted or unsubstituted carbamoyloxy group,R²denotes a halogen atom; a lower alkyl group; or a cycloalkyl orcycloalkenyl group optionally substituted by a lower alkyl group, ahydroxyl group, an acyloxy group or an oxo group, R³ and R⁴ each denotea hydrogen atom or a lower alkyl group, or R³ and R⁴ combine with thenitrogen atom to which they bind, to denote a heterocyclic ring whichmay further contain a hetero atom'selected from O, S and N, A denotes Oor CH₂, B denotes C═O or CH₂, and n denotes 1 or
 2. 2. Thebenzothiophene derivative or the salt thereof according to claim 1wherein R² denotes a group of the formula ##STR18## (wherein R⁵ and R⁶each denote a lower alkyl group) or a cycloalkyl group having 3 to 8carbon atoms optionally substituted by a lower alkyl group or a hydroxylgroup.
 3. The benzothiophene derivative or the salt thereof according toclaim 2 wherein R³ and R⁴ each denote a lower alkyl group, or R³ and R⁴combine with the nitrogen atom to which they bind to denote a 5- to7-membered heterocyclic group.
 4. The benzothiophene derivative or thesalt thereof according to claim 3 wherein R¹ denotes a hydroxyl group.5. The benzothiophene derivative or the salt thereof according to claim4 wherein A denotes O and B denotes CH₂.
 6. The benzothiophenederivative or the salt thereof according to claim 5 which is(6-hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone,(6-hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone,(6-hydroxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone,(6-hydroxy-2-cycloheptylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone,(6-hydroxy-2-isopropylbenzo[b]thien-3-yl)4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanoneor (6-hydroxy-2-isopropylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone.7. The benzothiophene derivative or the salt thereof according to claim4 wherein A denotes CH₂.
 8. The benzothiophene derivative or the saltthereof according to claim 7 which is(6-hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-pyrrolidinyl)propyl]phenyl]methanone,(6-hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propyl]phenyl]methanoneor(6-hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinylcarbonyl)ethyl]phenyl]methanone.9. The benzothiophene derivative or the salt thereof according to claim3 wherein R¹ denotes a lower alkoxyl group or a lower alkylcarbonyloxygroup.
 10. The benzothiophene derivative or the salt thereof accordingto claim 9 which is(6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxyl]phenyl]methanoneor(6-acetoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone.11. An antiestrogenic agent containing a benzothiophene derivativeaccording to claim 1 or a salt thereof.